Thoracic ossification of the human ligamentum flavum: histopathological and immunohistochemical findings around the ossified lesion

Yayama, Takafumi; Uchida, Kenzo; Kobayashi, Shigeru; Kokubo, Yasuo; Sato, Ryuichiro; Nakajima, Hideaki; Takamura, Takaharu; Bangirana, Alexander; Itoh, Hiroshi; Baba, H.

doi:10.3171/spi-07/08/184

Cited by 107 publications

(102 citation statements)

References 28 publications

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“…7,13,19,22,27 It commonly affects the lower thoracic spine, especially T9-L1. 7,15,19,20,26 This is consistent with the preoperative imaging results from our study. The exact cause of OLF has not been conclusively established.…”

Section: Discussionsupporting

confidence: 91%

Upper facet joint en bloc resection for the treatment of thoracic myelopathy caused by ossification of the ligamentum flavum

Yang¹,

Xue²,

Dai³

et al. 2013

SPI

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Object The authors introduce a novel technique to treat thoracic myelopathy caused by ossification of the ligamentum flavum (OLF): upper facet joint en bloc resection. This surgical procedure avoids surgery to the most heavily compressed cord surface, contact with the cord, and cord injury. The epidural venous plexus bleeding point can be directly seen and easily controlled during the decompression. Methods Between January 2007 and January 2009, thoracic myelopathy caused by OLF was diagnosed in 38 patients using plain radiography, CT, and MRI, and diagnoses were confirmed by postoperative pathological examination. All upper facet joint en bloc resection procedures were performed in 2 steps. First, the bony structures above the upper facet joint surfaces were resected and the upper facet joints were isolated. Second, en bloc resection of the upper facet joint was performed by dissection of the junction between the pedicle and upper facet joint. Intraoperative neurological monitoring was performed in all cases. The modified Japanese Orthopaedic Association (mJOA) scoring system was used to assess neurological status. The degree of postoperative expansion of the spinal cord was calculated on axial MR images. The pre- and postdecompression Cobb angle was applied to assess the magnitude of local kyphosis. Results Of the 38 cases of OLF, 6 were single level, 12 were double level, and 20 were multilevel. Of the 92 ossified segments in this study, 23 (25.0%) were located in the upper thoracic spine (T1–4), 13 (14.1%) were located in the midthoracic spine (T5–8), and 56 (60.9%) were located in the lower thoracic spine (T9–L1). The mean intraoperative blood loss was 340 ± 54 ml. The neurological status improved during follow-up (mean 46.1 months) from a preoperative mean mJOA score of 5.39 ± 1.52 to 8.97 ± 1.22 points (t = 18.39, p < 0.05). The neurological function recovery rate ranged from 28.6% to 100%. The mean increase in pre- and postoperative kyphosis of the involved vertebrae was only 1.3° ± 1.6°. The increase in the cross-sectional area of the dural sac at the level of maximum compression suggested that decompression was complete. Conclusions Upper facet joint en bloc resection is effective and may be a reasonable alternative treatment choice for thoracic myelopathy caused by OLF.

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Section: Discussionsupporting

confidence: 91%

Upper facet joint en bloc resection for the treatment of thoracic myelopathy caused by ossification of the ligamentum flavum

Yang¹,

Xue²,

Dai³

et al. 2013

SPI

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“…These characteristics were similar to clinical OLF. 22,28 There were puzzling features of this OLF model. None of the rats evaluated showed any gait disturbance or paralysis during the observation period, even though the spinal canal was severely encroached and the spinal cord was clearly distorted.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human bone morphogenetic protein-2–induced ossification of the ligamentum flavum in rats and the associated global modification of histone H3

Huang

Fan²,

Sun³

et al. 2014

SPI

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Object The primary object of this investigation was to study recombinant human bone morphogenetic protein–2 (rhBMP-2)–induced ossification of the ligamentum flavum and associated histone H3 modification in a rat model. In an additional set of studies the authors investigated spinal cord and behavioral changes in the same model. Methods The authors report on 2 separate sets of studies. A total of 90 rats were used for the 2 sets of studies (45 each); in each study, a lyophilized rhBMP-2 and collagen mixture (20 μg rhBMP-2 and 200 μl collagen) was implanted in the lumbar extradural space in 18 rats; another 18 animals were used for a sham-operation control group and underwent implantation of lyophilized collagen without rhBMP-2 at the same level; an additional 9 animals were used as untreated controls. Lumbar spinal samples were harvested from the rhBMP-2 groups and the shamoperation control groups at 1 week, 3 weeks, and 9 weeks after the operation. Samples were also obtained from untreated controls at the same time points. All samples were scanned using micro-CT and then made into paraffinembedded sections. The sections from the first set of 45 rats were stained using elastica van Gieson and toluidine blue, and the expression of histone modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) and osteogenic transcription factors (osterix, Runx2) was detected by immunohistochemistry. In the second set of studies, hindlimb motor function was assessed at 1 week, 3 weeks, and 9 weeks after surgery. After behavioral evaluation, samples were harvested, scanned using micro-CT, and then made into paraffin-embedded sections. The sections were stained using Luxol fast blue. The expression of NeuN was also detected using immunohistochemistry. Results Ossification was seen in the rhBMP-2 group from 1 week after insertion, and the volume of ossified mass increased at 3 and 9 weeks. There was no ossification seen in the sham-surgery and normal controls. The pathological changes of ossification involved ligament degeneration, cartilage formation, and, finally, bone replacement. Spinal cord evaluation showed a significant decrease in white matter content and number of neurons at 9 weeks after operation in the rhBMP-2–treated group (compared with findings in the sham-surgery and control groups as well as findings at the earlier time points in the rhBMP-2 group). Using immunohistochemical staining, histone modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) and osteogenic transcription factors (osterix, Runx2) all were found to be expressed in the fibrocartilage area of the rat ossified ligamentum flavum samples (rhBMP2 group). Conclusions This rhBMP-2–induced OLF is a typical endochondral ossification, which is similar to clinical OLF. The compressed spinal cord around the ossification site showed signs of a chronic degenerative process. Histone H3 modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) may play an important role in OLF.

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“…OLF is a well-recognized cause of spinal canal stenosis resulting in myeloradiculopathy, particularly in Asian population [2]. Previous studies have suggested that some factors, such as genetic background [3], diabetes mellitus [4], fluorosis [5], ankylosing spondylitis [6], mechanical stress [7] and regional cytokines or growth factors [8,9], were involved in the onset and progression of OLF, but the underlying pathogenesis of this disease is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Growth/differentiation Factor-5 Induces Osteogenic Differentiation of Human Ligamentum Flavum Cells through Activation of ERK1/2 and p38 MAPK

Zhong

Chen

Zhang

et al. 2010

Cell Physiol Biochem

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Ossification of ligamentum flavum (OLF) is a pathological ectopic ossification in the spinal ligament, leading to spinal canal stenosis, but little was known about its pathogenesis. A previous study has found growth/differentiation factor (GDF)-5 expression at ossified sites of the ligaments from OLF patients. This study aimed to investigate the osteogenic effects of GDF-5 on cultured human ligamentum flavum cells (LFCs). LFCs were isolated from human spinal ligamentum flavum, and treated with or without recombinant human (rh) GDF-5. Alkaline phosphatase (ALP) activity was measured. Expression of osteocalcin was assessed by reverse transcriptase-PCR, Western blotting and immunofluorescence. Matrix mineralization was assessed by alizarin red staining. Activation of mitogen-activated protein kinases (MAPK) ERK1/2, p38 and JNK were detected by Western blotting. We found that rhGDF-5 treatment increased ALP activity and osteocalcin expression in a time-and dosedependent manner, and induced mineralized nodule form. In addition, rhGDF-5 challenge mediated the ERK1/2 and p38 activation but not JNK. Inhibiting this activation pharmacologically, using U0126, a ERK1/ 2 inhibitor, or SB203580, a p38 inhibitor, resulted in significantly lower ALP activity and osteocalcin protein expression. The present study shows that rhGDF-5 induces osteogenic differentiation of human LFCs through activation of ERK1/2 and p38 MAPK. These findings give some new insight into the pathogenesis of OLF.

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Thoracic ossification of the human ligamentum flavum: histopathological and immunohistochemical findings around the ossified lesion

Cited by 107 publications

References 28 publications

Upper facet joint en bloc resection for the treatment of thoracic myelopathy caused by ossification of the ligamentum flavum

Upper facet joint en bloc resection for the treatment of thoracic myelopathy caused by ossification of the ligamentum flavum

Recombinant human bone morphogenetic protein-2–induced ossification of the ligamentum flavum in rats and the associated global modification of histone H3

Growth/differentiation Factor-5 Induces Osteogenic Differentiation of Human Ligamentum Flavum Cells through Activation of ERK1/2 and p38 MAPK

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